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Design, Synthesis and Bioevaluation of an EphA2 Receptor‐Based Targeted Delivery System
Author(s) -
Barile Elisa,
Wang Si,
Das Swadesh K.,
Noberini Roberta,
Dahl Russell,
Stebbins John L.,
Pasquale Elena B.,
Fisher Paul B.,
Pellecchia Maurizio
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201400067
Subject(s) - paclitaxel , chemistry , peptide , drug delivery , conjugate , drug , eph receptor a2 , pharmacology , targeted drug delivery , linker , cancer research , receptor , cancer , medicine , biochemistry , computer science , mathematical analysis , mathematics , organic chemistry , receptor tyrosine kinase , operating system
Abstract Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2‐targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long‐lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate‐limiting degradation sites on the peptide–drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide–drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells.